Multiple sclerosis (MS) is the most common acquired neurologic disease of young adults in we, stem Europe and North America. It accounts for more disability and financial loss, both in lost income and in medical care, than any other neurologic disease of this age group. There are approximately 250.000 cases of MS in the United States.
MS affects the central nervous system and involves a demyelination process i.e. the myelin sheats are lost whereas the axons are preserved. In the central nervous system (CNS), oligodendrocytes send out processes to axons that envelope them with layers of plasma membrane that are compacted and then constitute the myelin. Myelin provides the isolating material that enables rapid nerve impulse conduction. Evidently, in demyelination, this property is lost. Although the pathogenic mechanisms responsible for MS are not understood, several lines of evidence indicate that demyelination has an immunopathologic basis. The pathologic lesions, the plaques, are characterized by infiltration of immunologically active cells such as plasma cells, macrophages and activated T cells (1). The T cells present in the cerebrospinal fluid of MS patients during acute attacks have been reported to be oligoclonal as judged by their T cell receptor usage, a finding which indicate a response to a particular antigen (2). The latter suggestion is also supported by immunogenetic studies showing an association of MS with certain MHC class II alleles (3). Increased cerebrospinal fluid immunoglobulin is consistently found in MS (4), and a variety of abnormalities in T cell functions have been described (5).
The ultimate treatment of MS would be the repair of damaged CNS myelin. Although there is no indication that the goal will be achieved soon, recent advances in understanding the biology of glial cells (which manufacture and maintain myelin) suggest that such treatment may be feasible eventually. Current treatment of MS falls into three categories: treatment of acute exacerbations, modulation of progressive disease, and therapy for specific symptoms.
Corticosteroids and ACTH have been shown to be useful in shortening the mount of time required for recovery from an exacerbation of MS. The mechanism of this effect is unknown. These medications do not increase the extent of recovery, nor do they prevent subsequent exacerbations. It has been established recently that corticosteroids are as useful as ACTH for treatment of acute exacerbations. Neither medication has been shown to be beneficial in chronic administration. Use of corticosteroids should be reserved for the treatment of dear-cut neurologic signs that are disabling. For the treatment of life-threatening exacerbations, most commonly, involving brain stem compromise, methylprednisolone in large doses (1 g IV daily for three days) has been used.
Hyperbaric oxygen treatment has recently been shown in several well-controlled trials to be completely ineffective as a treatment for all forms of MS. The antiviral substance transfer factor has been shown to be ineffective in a limited trial.
Since the immune system is believed to be involved in the development of the pathogenic process in MS, the use of immunosuppressive therapy has recently received widespread attention. Cyclophosphamide, administered in a regimen sufficient to induce lymphopenia, has been demonstrated to stabilize symptoms in patients with chronic progressive MS. Unfortunately, the effect is transient and treated and control patients are indistinguishable 3 years after treatment (6). Other general immunosuppressive treatment such as total lymphoid irradiation or treatment with azathioprine has only resulted in slight effects on symptoms (7, 8). Recently, a large multicenter trial of cyclosporine A indicates that this treatment slows the profession of the disease (9). More specific immunosuppressive treatment of MS is currently being evaluated in clinical trials and include monoclonal antibodies to T cell populations, vaccination against T cells or low dose heparin to prevent migration of T cells into the central nervous system (5). A common denominator of all these treatment regimen is that they are immunosuppressive and the rationale of their use is to suppress immune reactivity against nervous-tissue.
Quinoline-3-carboxamide compounds have been suggested as pharmaceuticals in the prior art. These compounds comprise the structure given in formula I below, optionally with substituents for the hydrogens H.sup.1-9, and where appropriate, pharmaceutically and physiologically acceptable and therapeutically active salts of the compounds. ##STR2##
Formula I is a collective formula for the tautomeric structures II-IV. ##STR3## In these formulae (a) ------------ represents that there are two conjugated double bonds between atoms comprised by the dashed line (only formula I).
(b) The hydrogens H.sup.7 and H.sup.8 are attached to different atoms selected from X.sub.1, X.sub.2 and the nitrogen atom in the quinoline ring PA1 (c) X.sub.1 and X.sub.2 are independently selected from an oxygen atom or an NH.sup.9 group, said X.sub.1 and X.sub.2 being bound by a single bond to the ring when carrying H.sup.7 or H.sup.8 and by a double bond when not carrying H.sup.7 or H.sup.8.
The substituents that, according to the prior art, my replace H.sup.1-9 can in principle be any substituent that gives compounds that can be isolated. See for instance Indian journal of Chemistry Vol 17B (1979) 488-90 (and-inflammatory properties), U.S. Pat. No. 3,960,868 (=GB 1,467,061, analgesic, anticonceptive, anti-inflammatory and anti-allergic properties), U.S. Pat. No. 4,547,511 and U.S. Pat. No. 4,738,971 (enhancing cell-mediated immunity), WO 9015052 (U.S. Ser. No. 651,234, filed May 31, 1990, immune modulator), U.S. Pat. No. 4,107,310 (analgetics) and JP 68023948 (bacteriocides). US patents and patent applications given above are hereby imcorporated by reference. In general it can be stated that many of the compounds comprised by formula I are classified as immune modulators with individual effects spanning the spectra from suppression to stimulation of the immune system. The specific effect achieved depends on the substituents.
Among the compounds of formula I, N-phenyl-N-methyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline -3-carboxamide Linomide.RTM., LS 2616 with the generic name roquinimex) and its salts as defined above have ,for the time being appeared the most promising drug candidate i.e. a compound of structure II with a phenyl substituent for H.sup.1, a methyl substituent for each of H.sup.2 and H.sup.8 (H.sup.8 being attached to the nitrogen atom of the quinoline ring), with no substituents for H.sup.3-7 and H.sup.7 attached to X.sub.1, and each of X.sub.1 and X.sub.2 being an oxygen atom. The compound has double bonds between positions 3 and 4 and between positions 2 and X.sub.2 positions refer to those of the quinoline ring).
The scientific experimentation with roquinimex has shown that the compound has multiple immunological activities. It has thus been found that roquinimex increases the proliferative response to T and B cell mitogens (10), enhances antibody production (11) and augments NK cell activity (12). Moreover, its immunostimulating properties may be useful in the treatment of tumours (14), and systemic lupus erythematosus (15) as suggested in U.S. Pat. Nos. 4,547,511 and 4,738,971. During the priority year our results with roquinimex (Linomide.RTM.) have been published (16-19).